NOD2 Deficiency Promotes Intestinal CD4+T Lymphocyte Imbalance, Metainflammation, and Aggravates Type 2 Diabetes in Murine Model

被引:25
作者
Carlos, Daniela [1 ]
Perez, Malena M. [1 ]
Leite, Jefferson A. [1 ]
Rocha, Fernanda A. [1 ]
Martins, Larissa M. S. [1 ]
Pereira, Camila A. [2 ]
Fraga-Silva, Thais F. C. [1 ]
Pucci, Tais A. [1 ]
Ramos, Simone G. [3 ]
Camara, Niels O. S. [4 ]
Bonato, Vania L. D. [1 ]
Tostes, Rita C. [2 ]
Silva, Joao S. [1 ,5 ]
机构
[1] Univ Sao Paulo, Dept Biochem & Immunol, Ribeirao Preto, Brazil
[2] Univ Sao Paulo, Dept Pharmacol, Ribeirao Preto, Brazil
[3] Univ Sao Paulo, Dept Pathol & Legal Med, Ribeirao Preto Med Sch, Ribeirao Preto, Brazil
[4] Univ Sao Paulo, Inst Biomed Sci ICB, Dept Immunol, Ribeirao Preto, Brazil
[5] Fiocruz Biinst Translat Med Plataform, Ribeirao Preto, Brazil
基金
巴西圣保罗研究基金会;
关键词
Innate immunity receptor; helper T lymphocytes; metainflammation; gut microbiota; obesity and type 2 diabetes; REGULATORY T-CELLS; INSULIN-RESISTANCE; GUT MICROBIOTA; DENDRITIC CELLS; ADIPOSE-TISSUE; INFLAMMATION; OBESITY; EXPRESSION; FAT; RECOGNITION;
D O I
10.3389/fimmu.2020.01265
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Type 2 diabetes (T2D) is a metabolic disease characterized by increased inflammation, NOD-like receptors (NLRs) activation and gut dysbiosis. Our research group has recently reported that intestinal Th17 response limits gut dysbiosis and LPS translocation to visceral adipose tissue (VAT), protecting against metabolic syndrome. However, whether NOD2 receptor contributes intestinal Th17 immunity, modulates dysbiosis-driven metabolic tissue inflammation, and obesity-induced T2D remain poorly understood. In this context, we observed that mice lacking NOD2 fed a high-fat diet (HFD) display severe obesity, exhibit greater adiposity, and more hepatic steatosis compared to HFD-fed wild-type (WT) mice. In addition, they develop increased hyperglycemia, worsening of glucose intolerance, and insulin resistance. Notably, the deficiency of NOD2 causes a deviation from M2 macrophage and regulatory T cells (Treg) to M1 macrophage and mast cells into VAT compared to WT mice fed HFD. An imbalance was also observed in Th17/Th1 cell populations, with reduced IL-17 and IL-22 gene expression in the mesenteric lymph nodes (MLNs) and ileum, respectively, of NOD2-deficient mice fed HFD. 16S rRNA sequencing indicates lower richness, alpha diversity, and a depletion ofAllobaculum, Lactobacillus, and enrichment withBacteroidesgenera in these mice compared to HFD-fed WT mice. These alterations were associated with disrupted tight-junctions expression, augmented serum LPS, and bacterial translocation into VAT. Overall, NOD2 activation is required for a protective Th17 over Th1 immunity in the gut, which seems to decrease gram-negative bacteria outgrowth in gut microbiota, attenuating the endotoxemia, metainflammation, and protecting against obesity-induced T2D.
引用
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页数:16
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